NM_052936.5:c.527C>T

Variant names:

• chrX-108137150-C-T
• rs747774203
• NM_052936.5:c.527C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_052936.5(ATG4A):​c.527C>T​(p.Thr176Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000332 in 1,204,803 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: ATG4A NM_052936.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.12
• Publications: 0 publications found

Genes affected

ATG4A (HGNC:16489): (autophagy related 4A cysteine peptidase) Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed. This gene encodes a member of the autophagin protein family. The encoded protein is also designated as a member of the C-54 family of cysteine proteases. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052936.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4A	NM_052936.5	MANE Select	c.527C>T	p.Thr176Ile	missense	Exon 7 of 13	NP_443168.2
	ATG4A	NM_178270.4		c.527C>T	p.Thr176Ile	missense	Exon 7 of 12	NP_840054.1	Q8WYN0-2
	ATG4A	NM_001321287.2		c.296C>T	p.Thr99Ile	missense	Exon 8 of 14	NP_001308216.1	Q8WYN0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4A	ENST00000372232.8	TSL:1 MANE Select	c.527C>T	p.Thr176Ile	missense	Exon 7 of 13	ENSP00000361306.3	Q8WYN0-1
	ATG4A	ENST00000345734.7	TSL:1	c.527C>T	p.Thr176Ile	missense	Exon 7 of 12	ENSP00000298131.5	Q8WYN0-2
	ATG4A	ENST00000372246.7	TSL:1	n.*685C>T		non_coding_transcript_exon	Exon 8 of 14	ENSP00000361320.3	F8W7J2

Frequencies

GnomAD3 genomes AF: 0.00000886 AC: 1 AN: 112870 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000276

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000167 AC: 3 AN: 179833 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1091933 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 357633

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26226

American (AMR) AF: 0.00 AC: 0 AN: 34859

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19214

East Asian (EAS) AF: 0.000101 AC: 3 AN: 29820

South Asian (SAS) AF: 0.00 AC: 0 AN: 53480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40211

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4111

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838194

Other (OTH) AF: 0.00 AC: 0 AN: 45818

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0953088), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000886 AC: 1 AN: 112870 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 35036

African (AFR) AF: 0.00 AC: 0 AN: 31058

American (AMR) AF: 0.00 AC: 0 AN: 10727

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.000276 AC: 1 AN: 3620

South Asian (SAS) AF: 0.00 AC: 0 AN: 2731

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6217

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53412

Other (OTH) AF: 0.00 AC: 0 AN: 1528

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	0.000065	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.31
Sift	Benign	0.11	T
Sift4G	Benign	0.19	T
Polyphen		0.62	P
Vest4		0.93
MutPred		0.72		Loss of loop (P = 0.0986)
MVP		0.59
MPC		1.2
ClinPred		0.71	D
GERP RS		6.1
Varity_R		0.65
gMVP		0.87
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs747774203; hg19: chrX-107380380;